Mitochondrial redox adaptations enable alternative aspartate synthesis in SDH-deficient cells
- Fred Hutchinson Cancer Research Center, United States
- New Mexico State University, United States
Abstract
The oxidative tricarboxylic acid (TCA) cycle is a central mitochondrial pathway integrating catabolic conversions of NAD+ to NADH and anabolic production of aspartate, a key amino acid for cell proliferation. Several TCA cycle components are implicated in tumorigenesis, including loss of function mutations in subunits of succinate dehydrogenase (SDH), also known as complex II of the electron transport chain (ETC), but mechanistic understanding of how proliferating cells tolerate the metabolic defects of SDH loss is still lacking. Here, we identify that SDH supports human cell proliferation through aspartate synthesis but, unlike other ETC impairments, the effects of SDH inhibition are not ameliorated by electron acceptor supplementation. Interestingly, we find aspartate production and cell proliferation are restored to SDH-impaired cells by concomitant inhibition of ETC complex I (CI). We determine that the benefits of CI inhibition in this context depend on decreasing mitochondrial NAD+/NADH, which drives SDH-independent aspartate production through pyruvate carboxylation and reductive carboxylation of glutamine. We also find that genetic loss or restoration of SDH selects for cells with concordant CI activity, establishing distinct modalities of mitochondrial metabolism for maintaining aspartate synthesis. These data therefore identify a metabolically beneficial mechanism for CI loss in proliferating cells and reveal how compartmentalized redox changes can impact cellular fitness.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files; Source Data files have been provided for Figures 1-8.
Article and author information
Author details
Funding
National Cancer Institute (P30CA015704)
- Lucas B Sullivan
National Institute of General Medical Sciences (T32GM095421)
- Madeleine L Hart
National Cancer Institute (R00CA218679-03S1)
- Madeleine L Hart
National Cancer Institute (R00CA218679)
- Lucas B Sullivan
National Institute of General Medical Sciences (R35GM147118)
- Lucas B Sullivan
Andy Hill Cancer Research Endowment (CARE Award)
- Lucas B Sullivan
National Cancer Institute (U54CA132381)
- Samantha M Carlisle
- Lucas B Sullivan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Mark S Sharpley, Cedars-Sinai Medical Center, United States
Ethics
Animal experimentation: All mouse work was performed in accordance with FHCC-approved IACUC protocol 51069 and AAALAS guidelines and ethical regulations.
Version history
- Preprint posted: March 14, 2022 (view preprint)
- Received: March 15, 2022
- Accepted: March 6, 2023
- Accepted Manuscript published: March 8, 2023 (version 1)
- Accepted Manuscript updated: March 9, 2023 (version 2)
- Version of Record published: March 20, 2023 (version 3)
Copyright
© 2023, Hart et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Mitochondrial redox adaptations enable alternative aspartate synthesis in SDH-deficient cells
eLife 12:e78654.
https://doi.org/10.7554/eLife.78654
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